Molecule Information

General Information of the Molecule (ID: Mol04016)

• Name: Aurora kinase A (AURKA) ,Homo sapiens
• Synonyms: Aurora 2; Aurora/IPL1-related kinase 1; Breast tumor-amplified kinase; Ipl1- and aurora-related kinase 1; Serine/threonine-protein kinase 15; Serine/threonine-protein kinase 6; Serine/threonine-protein kinase Ayk1; Serine/threonine-protein kinase aurora-A
• Molecule Type: Protein
• Gene Name: AURKA
• Gene ID: 6790
• Location: chr20:56369389-56392337[-]
• Sequence:
  MDRSKENCISGPVKATAPVGGPKRVLVTQQFPCQNPLPVNSGQAQRVLCPSNSSQRIPLQ
  AQKLVSSHKPVQNQKQKQLQATSVPHPVSRPLNNTQKSKQPLPSAPENNPEEELASKQKN
  EESKKRQWALEDFEIGRPLGKGKFGNVYLAREKQSKFILALKVLFKAQLEKAGVEHQLRR
  EVEIQSHLRHPNILRLYGYFHDATRVYLILEYAPLGTVYRELQKLSKFDEQRTATYITEL
  ANALSYCHSKRVIHRDIKPENLLLGSAGELKIADFGWSVHAPSSRRTTLCGTLDYLPPEM
  IEGRMHDEKVDLWSLGVLCYEFLVGKPPFEANTYQETYKRISRVEFTFPDFVTEGARDLI
  SRLLKHNPSQRPMLREVLEHPWITANSSKPSNCQNKESASKQS
• 3D-structure: PDB ID: 2J4Z; Classification: Transferase; Method: X-ray diffraction; Resolution: 2.00 Å
• Function: Mitotic serine/threonine kinase that contributes to the regulation of cell cycle progression (PubMed:11039908, PubMed:12390251, PubMed:17125279, PubMed:17360485, PubMed:18615013, PubMed:26246606). Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis (PubMed:14523000, PubMed:26246606). Required for normal spindle positioning during mitosis and for the localization of NUMA1 and DCTN1 to the cell cortex during metaphase (PubMed:27335426). Required for initial activation of CDK1 at centrosomes (PubMed:13678582, PubMed:15128871). Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2 (PubMed:11551964, PubMed:14702041, PubMed:15128871, PubMed:15147269, PubMed:15987997, PubMed:17604723, PubMed:18056443, PubMed:18615013). Regulates KIF2A tubulin depolymerase activity (PubMed:19351716). Important for microtubule formation and/or stabilization (PubMed:18056443). Required for normal axon formation (PubMed:19812038). Plays a role in microtubule remodeling during neurite extension (PubMed:19668197). Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint- response pathways critical for oncogenic transformation of cells, by phosphorylating and destabilizing p53/TP53 (PubMed:14702041). Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity (PubMed:11551964). Inhibits cilia outgrowth (By similarity). Required for cilia disassembly via phosphorylation of HDAC6 and subsequent deacetylation of alpha-tubulin (PubMed:17604723, PubMed:20643351). Regulates protein levels of the anti-apoptosis protein BIRC5 by suppressing the expression of the SCF(FBXL7) E3 ubiquitin-protein ligase substrate adapter FBXL7 through the phosphorylation of the transcription factor FOXP1 (PubMed:28218735). .
• Uniprot ID: AURKA_HUMAN
• Ensembl ID: ENSG00000087586
• HGNC ID: HGNC:11393

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Clinical Trial Drug(s) 1 drug(s) in total

Alisertib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Glioblastoma [ICD-11: 2A00.02] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Alisertib
• Molecule Alteration: Autophosphorylation; Thr288
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: GBM22 PDX cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: SF188 PDX cells; Brain; Homo sapiens (Human); CVCL_6948
• In Vitro Model: Silenced PGC1alpha in GBM22 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: Silenced PGC1alpha in SF188 cells; Brain; Homo sapiens (Human); CVCL_6948
• In Vitro Model: Transfect T58A mutant c-Myc in GBM22 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: Transfected c-Myc in GBM22 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The response to Aurora kinase A inhibitors depends on glycolysis and that tumor cells with an oxidative metabolic phenotype will be more resistant to Aurora kinase A inhibitor treatment. Moreover, in a manner dependent on the transcription factors c-MYC and PGC1alpha treatment with Aurora kinase A inhibitors renders GBM cells highly oxidative and dependent on fatty acid oxidation that in turn mediates them to be susceptible to inhibitors of FAO in vitro and in vivo.

Disease Class: Glioblastoma [ICD-11: 2A00.02] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Alisertib
• Molecule Alteration: Autophosphorylation; Thr288
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: GBM22 orthotopic PDX model; orthotopic murine GBM model; subcutis of immunocompromised Nu/Nu mice, GBM12 cells; subcutis of immunocompromised Nu/Nu mice, GBM43 cells; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: The response to Aurora kinase A inhibitors depends on glycolysis and that tumor cells with an oxidative metabolic phenotype will be more resistant to Aurora kinase A inhibitor treatment. Moreover, in a manner dependent on the transcription factors c-MYC and PGC1alpha treatment with Aurora kinase A inhibitors renders GBM cells highly oxidative and dependent on fatty acid oxidation that in turn mediates them to be susceptible to inhibitors of FAO in vitro and in vivo.

References

• Ref 1: Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma. Nat Commun. 2021 Sep 1;12(1):5203.